As the title of the project implies, the relationship between the pancreatic hormone insulin and the Kupffer cells of the liver is under investigation. The influence of altering the level of circulating insulin on Kupffer cell phagocytosis is being studied. Hyperinsulinemia is achieved by injecting GIK (glucose-insulin-potassium) iv and hypoinsulinemia by injecting streptozotocin iv to produce experimental diabetes mellitus in rats. Kupffer cell phagocytosis is evaluated by carbon (8mg/100g iv) clearance. Blockade of Kupffer cells by prior phagocytosis of a variety of particulate materials (carbon, lipid, iron, bacteria) alters the availability of insulin to peripheral target cells in glucose-stimulated fasted rats. At 4 hr post-blockade hyperinsulinemia occurs in all experimental groups and is associated with enhanced glucose clearance. Hyperinsulinemia is due to a combination of enhanced pancreatic insulin secretion and depressed hepatic insulin extraction. The mechanisms of this response are under investigation. Experiments are planned to isolate the two major types of liver cells, i.e., hepatocytes and Kupffer cells. The presence of insulin receptors on and of insulin degrading enzymes in both hepatocytes and Kupffer cells is to be determined.